The present invention relates to the novel use of a group of specific amino acid derivatives according to Formula I for the preparation of pharmaceutical compositions useful for the treatment of allodynia as a major and unique pain symptom independent of the nature of an underlying disease, but that is often related to neuropathic pain or other different types of chronic or phantom pain. Particularly the present invention relates to the novel use of harkoseride and its derivatives for the preparation of pharmaceutical compositions useful for the treatment of allodynia as a major and unique pain symptom independent of the nature of an underlying disease, but that is often related to neuropathic pain, or other different types of chronic or phantom pain.
The chemical name of SPM 927 which is also hereinafter referred to as harkoseride is (R)-2-Acetamido-N-benzyl-3-methoxypropionamide.
The compounds of the invention are known agents useful in antiseizure therapy for central nervous system disorders such as epilepsy, stroke and cerebral ischemia.
The instant invention concerns the novel use of a compound of Formula I below for the preparation of pharmaceutical compositions useful for the treatment of pain, particularly for the treatment of chronic pain disorders and especially for the treatment of allodynia as a major and unique pain symptom independent of the nature of an underlying disease, but that is often related to neuropathic pain conditions, or other different types of chronic or phantom pain and tinnitus aureum.
According to the invention compounds are those of Formula I
or a pharmaceutically acceptable salt thereof wherein    Ar is phenyl which is unsubstituted or substituted with at least one halo group;    Q is lower alkoxy containing 1-3 carbon atoms and Q1 is methyl;    diastereomers and enantiomers of compounds of Formula I are Included in the invention.
Preferred compounds of the invention are those according to Formula I in which the compounds are an (R), (S), or (R,S) isomer.
The most preferred compound of the invention is (R)-2-Acetamido-N-benzyl-3-methoxypropionamide or its pharmaceutically acceptable salt thereof.
Pain is a subjective experience and the perception of pain is performed in particular parts of the Central Nervous System (CNS).
Usually noxious (peripheral) stimuli are transmitted to the Central Nervous System beforehand, but pain is not always associated with nociception.
A broad variety of different types of clinical pain exists, that are derived from different underlying pathophysiological mechanisms and that will need different treatment approaches.
The perception of pain may be characterized by three major types of clinical pain:                acute pain        chronic pain        neuropathic pain        
Acute clinical pain typically results from inflammation or soft tissue injury. This type of pain is adaptive and has the biologically relevant function of warning and enabling healing and repair of an already damaged body part to occur undisturbed. A protective function is achieved by making the injured/inflamed area and surrounding tissue hypersensitive to all stimuli so that contact with any external stimulus is avoided. The neuronal mechanisms underlying this type of clinical pain are fairly well understood and pharmacological control of acute clinical pain is available and effective by means of e.g. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) up to opioids depending on type and extension of the sensation.
Chronic clinical pain appears as sustained sensory abnormalities resulting from an ongoing peripheral pathology such as cancer of chronic inflammation (e.g. arthritis) or it can be independent of the initiating triggers. The latter being maladaptive, offering no survival advantage and very often no effective treatment is available.
Neuropathic pain is caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain includes, but is not limited to pain caused by nerve injury such as, for example, the pain diabetics suffer from.
Neuropathic pain shows two different pathophysiological mechanisms which have to be considered:
First, enhanced activity of afferent nociceptive neurons following sensitisation of (sleeping) neurons (e.g., inflammatory pain, cancer pain, headache, lower back pain, visceral pain, migraine) with the primary afferent nociceptive neuron remaining intact, though the receptor activity is changed and reduced thresholds, increase of firing rates and starting of or increase of spontaneous activity are typically found.
Second, ectopic activity of afferent nociceptive neurons following lesions of its axons (e.g., peripheral and central neuropathic pain), with the primary afferent neuron being damaged. This leads to irreversible peripheral and central biochemical, morphological and functional changes. Therefore, (peripheral) neuropathy is broadly defined as a disease of the (peripheral) nervous system.
There are several causes of human neuropathy with considerable variability in symptoms and neurological deficits. Painful neuropathies are defined as neurological disorders characterised by persistence of pain and hypersensitivity in a body region, of which the sensory innervation has been damaged, but damage to sensory nerves does not always produce neuropathic pain, usually loss of sensation rather than hypersensitivity or pain are observed.
Specific somatosensory disorders are referred to as allodynia (innocuous somatosensory stimulation evokes abnormal intense pain sensation with an explosive, radiating character often outlasting stimulus duration like a trigger), hyperalgesia (noxious stimulation evokes more intense and prolonged pain sensations), paresthesia (spontaneous aversive but nonpainful sensations, described as tingling or “pins and needles”), dysesthesia (evoked as well as spontaneous abnormal sensations).
Several key events are agreed in as common pathophysiological events of abnormal pain states particularely following peripheral nerve injury. Thus, high frequency spontaneous discharge from ectopic site is followed by an increased responsiveness of dorsal horn neurons and expansion of the receptive field, often defined as central sensitisation.
Common analgesics like opioids and non-steroidal anti-inflammatory drugs (NSAIDs) improve only insufficiently chronic abnormal pain syndromes. In the search for alternative treatment regimes to produce satisfactory and sustained pain relief, corticosteroids, conduction blockade, glycerol, antidepressants, local anesthetics, gangliosids and electrostimulation have been tried, but mainly anti-convulsants have been found useful against various types of neuropathic pain conditions, but appear to be most effective in cases of paroxysmal, lancinating events, e.g. trigeminal neuralgia.
If general overactivity and unleaded low threshold activation of sensory neurons is considered as one of the main syndromes of neuropathy and neuropathic pain sensation with a marked mechanoallodynia as the most disabling clinical sympton, selective inhibition of this pathophysiological event instead of general inhibition of high threshold noxious stimuli (by e.g. local anesthetics) of the normal sensory nociception provides clear advantages.
The conditions listed above are known to be poorly treated by currently marketed analgesics such as opioids or nonsteroidal anti-inflammatory drugs (NSAID's) due to insufficient efficacy or limiting side effects.
It is an object of this invention to provide a novel use of compounds according to the aforementioned Formula I and its derivatives for the preparation of pharmaceutical compositions useful for the treatment of allodynia as a major and unique pain symptom Independent of the nature of an underlying disease, but that is often related to neuropathic pain, or other different types of chronic or phantom pain.
Particularly it is an object of this invention to provide a novel use of harkoseride for the preparation of pharmaceutical compositions useful for the treatment of allodynia as a major and unique pain symptom independent of the nature of an underlying disease, but that is often related to neuropathic pain, or other different types of chronic or phantom pain.
Harkoseride, which chemical name is (R)-2-Acetamido-N-benzyl-3-methoxypropion-amide is one derivative selected of the group of specific amino acid derivatives.
This group of substances is disclosed in U.S. Pat. No. 5,378,729; U.S. Pat. No. 5,654,301 and 5,773,475. They show activity for the treatment of epilepsy and stroke. But there is no disclosure in the above references to make obvious the present invention.
The compounds of the present invention may form pharmaceutically acceptable salts with both organic and inorganic acids or bases.
For example, the acid addition salts of the basic compounds are prepared either by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution.
Examples of pharmaceutically acceptable salts are hydrochlorides, hydrobromides, hydrosulfates, etc. as well as sodium, potassium, and magnesium, etc. salts.
The compounds of the present invention can contain one or several assymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixtures thereof. The individual diastereomers or enantiomers may be prepared or isolated by methods already well-knwon in the art.
According to the invention it is preferred that the compounds are in the (R)-configuration. It is preferred that the compounds are substantially enantiopure. Most preferred is the compound (R)-2-Acetamido-N-benzyl-3-methoxypropionamide.
The compounds of this invention may be synthesized as disclosed in the documents U.S. Pat. No. 5,378,729; U.S. Pat. No. 5,654,301 and U.S. Pat. No. 5,773,475.
The compounds made by the synthetic methods can be used as pharmaceutical compositions as agent in the treatment of pain when an effective amount of a compound of the Formula I, together with a pharmaceutically acceptable carrier is used. The pharmaceutical can be used in a method for treating such disorders in mammals, including human, suffering therefrom by administering to such mammals an effective amount of the compounds described above in unit dosage form.
The pharmaceutical compound, made in accordance with the present invention, can be prepared and administered in a wide variety of dosage forms by either oral or parenteral routes of administration. For example, these pharmaceutical compositions can be made in inert, pharmaceutically acceptable carriers which are either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Other solid and liquid form preparations could be made in accordance with known methods of the art and administered by the oral route in an appropriate formulation, or by a parenteral route such as intravenous, intramuscular, or subcutaneous injection as a liquid formulation.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 2×300 mg per day per patient. A daily dose range of about 1 mg to about 300 mg is preferred. The dosages, however, may be varied depending upon the requirement with a patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for particular situations is within the skill of the art.
The following working examples selected from specific animal models show the anti-neuropathic pain activity of harkoseride and its derivatives in general and the antiallodynia efficay of harkoseride and its derivatives in particular.